We will investigate factors involved in the rate of metabolic and cardiovascular aging in men and women in the Fels Longitudinal Study (FLS). Although it is possible to age in good health, in the U.S. population progressive weight gain (Yanovski et al 2000) and an increasing prevalence of the metabolic syndrome are common attributes of aging. The prevalence of adults in the FLS with BMI >25kg/m2 increases from 30% in the fourth decade of life to 70% in the sixth decade, and the prevalence of the metabolic syndrome increase from 21% to 38% in men and from 14% to 34% in women the same age groups. Tempo of growth and development: We plan to ascertain the influence of a prolonged juvenile state, i.e., a retarded tempo of physiological development, on delaying the onset of the metabolic syndrome, cardiovascular disease (CVD), and type 2 diabetes mellitus (T2DM) later in life. To achieve this goal, we propose to link risk factors for these common but unhealthy features of aging to childhood tempo of physiological development. The tempo of physiological development will be determined in each subject by documenting his or her age at the time of the adiposity rebound;the onset of the pubertal growth spurt; the peak height velocity; menarche; and his or her bone age at each of these milestones. The temporal range of these milestones varies from 5 years for the adiposity rebound to nearly 8 years for menarche, and bone age may lag behind or jump ahead of chronological age by as much as 4.5 years in either direction. We plan to accomplish our objectives using long-term serial data collected from birth over periods as long as 75 years in 361 adult males and 354 adult females in the FLS. Juvenile protective factors: We also propose to examine levels of biomarkers measured in childhood and adolescence that are associated with a delayed onset of the metabolic syndrome, CVD, and T2DM. Such delays may be caused by the persistence of juvenile levels of protective factors into adulthood, or else by the persistence into adulthood of effects initiated by such factors in childhood. The biomarkers we will study include body composition, lipid profiles, adipokines, inflammatory markers, insulin resistance, insulin-like growth factor-1 (IGF-1), and adrenal androgens. We plan to identify which of these biomarkers measured during childhood and adolescence act to delay the onset of the metabolic syndrome, CVD, and T2DM and could be considered as juvenile protective factors. The proposed analysis of serial data collected over decades should reveal the natural history of the onset of the metabolic syndrome, CVD, and T2DM in relation to the tempo of growth and development during the first two decades of life and in relation to levels of biomarkers during childhood and adolescence that could be considered to be juvenile protective factors. We are examining features of childhood that prevent or delay the onset of unhealthy aspects of aging.